Administration of pharmaceutical formulations of peptides traditionally has been performed by injection, thereby avoiding drug degradation by the gastrointestinal tract. Injection, however, is generally regarded as being less than desirable, because of the immediate discomfort at the injection site, as well as because of long-term tissue damage that can be caused by repeated injections to a common area. Besides injection, other routes of administration include transdermal, intranasal, intratracheal, and pulmonary delivery.
Delivery of therapeutics through pulmonary routes is particularly advantageous. This approach eliminates the need for needles, limits irritation to the skin and body mucosa (common side effects of transdermally, iontophoretically, and intranasally delivered drugs), and eliminates the need for nasal and skin penetration enhancers (typical components of intranasal and transdermal systems that often cause skin or membrane irritations/dermatitis). Pulmonary administration is also economically attractive, amenable to patient self-administration, and is often preferred by patients over other alternative modes of administration.
However, pulmonary administration poses a number of difficulties that are not encountered in other routes of administration. For example, whereas intranasal or transdermal administration involves placing the drug to be absorbed in immediate or very close proximity to the actual point of absorption, pulmonary administration requires administering the drug several feet away from the actual point of absorption. Thus, a pulmonary formulation must survive a relatively long journey through the mouth, down the trachea, and into the lungs. If not properly formulated and delivered, the drug will not reach the site of absorption in the distal lungs, and availability is compromised.
The problems become even more complicated when a controlled or delayed release of the pulmonarily delivered drug is desired. A number of methods have been employed to control the release rate of drugs from pulmonary pharmaceutical compositions (see, e.g., Zeng, X. M., et al., “The controlled delivery of drugs to the lung,” Int. J. Pharmaceutics 124, 149-164 (1995)). Examples of these methods include, for example, the use of liposomes or biodegradable microspheres, and modification of the drug so that the active form of the drug is not readily released. Another method is to include the drug in an insoluble complex. For example, the injectable sustained release insulin formulations often contain insulin in a crystallized form, which releases insulin more slowly than compositions comprising free insulin. The insulin crystals that exhibit a satisfactory sustained release profile in injectable compositions, however, are not suitable for pulmonary delivery, because the crystals are too large and deposit prematurely before they reach the deep lung.
Glargine insulin, or insulin glargine, is an insulin analog that substitutes asparagine 21 of insulin with glycine, and adds two arginine residues to the C-terminus of the B chain of insulin. The molecular modification shifts the isoelectric point from pH 5.4 of insulin to pH 6.7 of glargine, and stabilizes the glargine hexamer. Therefore, at pH 4.0, insulin glargine is a clear, soluble solution. When insulin glargine is injected into tissue having physiological pH, the resulting change in pH causes the drug to precipitate. The formation of the precipitate, along with the increased stabilization of the insulin glargine hexamer, as well as inter-hexamer interaction, retards the absorption after injection, thereby resulting in a prolonged plasma level.
U.S. Published Application No. 2005/0084537, which is incorporated herein by reference in its entirety, discloses microparticles comprising a therapeutic agent, e.g., glargine, dispersed within a polymer matrix. The matrix comprises a first polymer of hyaluronic acid and a second polymer of either a non-ionic polymer, a polymeric gum, or a combination thereof. The microparticles may be formulated for nasal or pulmonary delivery.
Because of its unique physicochemical properties, glargine insulin presents additional challenges to formulating for pulmonary administration. The present invention is thus directed to the preparation of a formulation for pulmonary administration comprising insulin derivatives.